Toxoplasma gondii is an extremely common parasite of animals and humans and an important opportunistic pathogen in immunocompromised patients. Our previous studies indicate that strains of T. gondii from North America and Europe comprise just three highly clonal lineages. More recent studies indicate a very different population structure in South America, consisting of distinct lineages with greater genetic diversity. Increasingly, toxoplasmosis has been recognized as a cause of ocular infection in otherwise healthy individuals from South America, where most common parasite lineages are highly virulent in animal models. However, knowledge about the population structure of T. gondii from much of the world remains unavailable. Our studies indicate that lineages from North America an Europe are related by a recent common ancestry and the inheritance of a monomorphic version of chromosome 1a (Chr1a*). Surprisingly, Chr1a* also recently been spreading into the South, where it may be associated with expansion of a few successful lineages. We will explore the hypothesis that Chr1a* carries particular genes that impart increased fitness, hence leading to clonal expansion of lineages inheriting this chromosome. The spread of clonalilty in T. gondii may also have influenced transmission and pathogenicity, and hence understanding the population structure is of direct importance to human disease. The proposed studies will enlist an international consortium of investigators to define the population structure of T. gondii. We will examine the genetic diversity of T. gondii, map the spread of Chr1a*, and test models for the origin and expansion of clonal lineages. Expected outcomes include: 1) characterize the genetic composition of T. gondii strains using traditional and microarray-based sequencing technologies 2) define the major haplotypes that comprise the global population structure, 3) characterize prototypic isolates for each haplotype, and 4) test isolates in animal models for the traits of transmission and virulence. Classical and molecular genetic methods will also be employed to identify genes that have driven the recent and highly successful expansion of T. gondii isolates in animals and humans around the world. PUBLIC HEALTH RELEVANCE: Toxoplasma gondii has an highly unusual population structure and distinct lineages may be responsible for different clinical presentation in humans. The proposed studies will evaluate the global population structure of this parasite and define the biological traits, including transmission and virulence, of the major genotypes. The long term goal of these studies is to elucidate the molecular basis of the recent emergence of a few dominant lineages that cause the majority of human infections, which may facilitate development of improved detection methods and possible interventions against toxoplasmosis.